This invention relates to compositions containing vanadium (IV). More particularly, the invention relates to vanadium (IV) complexes containing a substituted or un-substituted catecholate ligand and having spermicidal activity.
The known spermicidal agents, nonoxynol-9 and gramicidin, exert their effects via a detergent-like ability to damage the sperm plasma membrane, perturb its conformation and destroy its semi-permeable nature thereby impairing the sperm motility and egg fertilizing functions (Wilborn, et al., Fertil Steril 1983; 39:717-719; Bourinbaiar, et al., Life Sci 1994; 54:PL 5-9). Because of their non-specific membrane disruptive properties, such vaginal spermicides have been shown to damage the cervicovaginal epithelium, as well, which may lead to a lower degree of protection from sexually transmitted diseases (Niruthisard, et al., Sex Transm Dis 1991; 18:176-179). A novel vaginal contraceptive preferably does not function with the non-specific membrane toxicity mediated by detergent-type action of the currently available vaginal contraceptives.
Vanadium is a physiologically essential element which can be found in one of five (I to V) oxidation states. Several inorganic salts containing vanadium with oxidation state +4 (IV) have been shown to function as modulators of cellular redox potential and to exert pleiotropic effects in multiple biological systems by catalyzing the generation of reactive oxygen intermediates. See, for example, Shi, et al., Ann Clin Lab Sci 1996; 26:390-49; Byczkowski, et al., Bull Environ Contam Toxicol 1988; 41:696-703; Younes, et al., Toxicology 1991,:66:63-74, and Sakurai, et al., Biochem Biophys Res Commun 1995; 206:133-137. Reactive oxygen intermediates have been reported to affect sperm motility by a combination of peroxidation of membrane lipids and proteins (Aitken, et al., Biol Reprod 1989; 40:183-197; Jones, et al., Fertil Steril 1979; 31:531-537). Peroxidative damage to the sperm plasma membrane is an important pathophysiological mechanism in the onset of male infertility (Aitken, et al., BioEssays 1994; 16:259-267). It has also been shown that superoxide radicals generated by the action of xanthine oxidase exert a direct, suppressive effect on many aspects of sperm function (Aitken, et al., J. Reprod. Fertil. 1993; 97:441-450). Sperm are thought to be particularly susceptible to oxidative stress by virtue of their high content of unsaturated fatty acids and their relative paucity of cytoplasmic enzymes for scavenging the reactive oxygen intermediates that initiate lipid peroxidation (Alvarez, et al., J Androl 1987; 8:338-348).
There is a need for new spermicidal compounds, compositions, and method for contraceptive purposes.
Vanadium (IV) complexes containing a substituted or un-substituted catecholate ligand have now been found to have potent, concentration-dependent spermicidal activity at micromolar concentrations. Examples of vanadium (IV) complexes containing a substituted or un-substituted catecholate ligand of the invention include complexes having the structure of Formula I, or pharmaceutically acceptable salts thereof. 
wherein R1, R2, R3 and R4 are the same or different and are independently selected from H, halo, OH2, O3SCF3, N3, CN, OCN, SCN, SeCN, NO2, C1-4 alkyl, C1-C4 alkoxy, and aryl; and n is 0 or 1; and R5 and R6 are the same or different and are either monodentate ligands or R5 and R6 together comprise a bidentate ligand.
Suitable monodentate ligands include, for example, aryl, halo, H2O, 3SCF3, N3, COOH, CN, OCN, SCN, SeCN, NO2, C1-C4 alkyl, C1-4 alkoxy. Preferred monodentate ligands comprises one or more unsubstituted or substituted aromatic ring. More preferred monodentate ligands comprise substituted or un-substituted cyclopentadienyl ligands.
Suitable bidentate ligands include, for example, N,Nxe2x80x2; N,O; and O,Oxe2x80x2 bidentate ligands. Examples of suitable N,Nxe2x80x2 bidentate ligands include diamines and other such known suitable N,Nxe2x80x2 bidentate ligands. Examples of diamines include bipyridal, derivatives of bipyridal, bridged bipyridal, such as phenanthroline, derivatives of phenanthroline, and other such compounds. Examples of suitable N,O bidentate ligands include amino acids and Schiff base type groups. Examples of suitable O,Oxe2x80x2 bidentate ligands include dicarboxylate, 2-hydroxyacetophenone, acetylacetone type and catechol type groups. Preferred bidentate ligands comprise one or more aromatic ring. Preferred examples of suitable bidentate ligands comprising aromatic rings include substituted or un-substituted bipyridyl, bridged bipyridyl, and acetophenone ligands. One example of a bridged bipyridyl includes phenanthroline.
In one embodiment the invention provides xe2x80x9cbent sandwichxe2x80x9d vanadocene monocatecholate complexes having the structure of Formula II, or pharmaceutically acceptable salts thereof. 
wherein Cp is unsubstituted cyclopentadienyl, or cyclopentadieneyl substituted with one or more substituents selected from substituted or unsubstituted aryl, C1-C4 alkyl, C1-C4 alkoxy, halo, OH2, O3SCF3, N3, CN, OCN, SCN, SeCN, NO2. Preferably, Cp is unsubstituted cyclopentadienyl.
R1, R2, R3 and R4 are the same or different and are independently selected from H, halo, OH2, O3SCF3, N3, CN, OCN, SCN, SeCN, NO2, C1-C4 alkyl, and C1-C4 alkoxy. Preferably, electron donating groups, for example electron donating alkyl groups, are present as substituitents of the catecholate ring in positions R1, R2, R3 and/or R4.
Another suitable embodiment of the invention having a bidentate ligand wherein the bidentate ligand is a bipyridyl has the general formula III, shown below, or pharmaceutically acceptable salts thereof: 
where R7 and R8 are the same or different and are independently selected from: H, aryl, C1-C4 alkyl, halo, C1-C4 alkoxy, cyano, and nitro; n is 0 or 1; R1, R2, R3 and R4 are the same or different and are independently selected from H, halo, OH2, O3SCF3, N3, CN, OCN, SCN, SeCN, N02, C1-C4 alkyl, and C1-4 alkoxy.
Another suitable embodiment of the invention having a bidentate ligand wherein the bidentate ligand is abridged bipyridyl has the general formula IV, shown below, or pharmaceutically acceptable salts thereof. 
where R9 and R10 are the same or different and are selected from H, aryl, C1-C4 alkyl, halogen, C1-C4 alkoxy, halogenated alkyl, cyano, and nitro; Z is selected from O, CH2, CH2-CH2, and CHxe2x95x90CH; n is 0 or 1; and halo, OH2, O3SCF3, N3, CN, OCN, SCN, SeCN, NO2, C1-C4 alkyl, and C1-4alkoxy.
Another suitable embodiment of the invention having a bidentate ligand. wherein the bidentate ligand is a bridged bipyridyl, and the bridged bipyridyl is phenanthroline, has the general formula V, shown below, or pharmaceutically acceptable salts thereof: 
where R11, R12 and R13 are the same or different arid are independently selected from: H, aryl, C1-C4 alkyl, halogen, lower alkoxy, halogenated alkyl, cyano, carboalkoxy (e.g. C2-C6) and nitro; n is 0 or 1; and R1, R2, R3 and R4 are the same or different and are independently selected from H, halo, OH2, O3SCF3, N3, CN, OCN, SCN, SeCN, NO2, C1-C4 alkyl, and C1-C4 alkoxy.
Another suitable embodiment of the invention having a bidentate ligand wherein the bidentate ligand is an O,Oxe2x80x2 bidentate ligand, and the complex has the general formula VI, is shown below, or pharmaceutically acceptable salts thereof: 
where R14 and R16 are the same or different and are independently selected from: H, aryl, C1-C4 alkyl, and C1-C4 alkoxy, arid halogenated alkyl; R15 is selected from H, C1-C4 alkyl, halo, C1-C4 alkoxy, and halogenated alkyl; n is 0 or 1; and R1, R2, R3 and R4 are the same or different and are independently selected. from H, halo, OH2, O3SCF3, N3, CN, OCN, SCN, SeCN, NO2, C1-C4 alkyl and C1-4alkoxy.
Accordingly, the present invention includes spermicidal vanadium (IV) complexes containing a substituted or un-substituted catecholate ligand, as well as contraceptive compositions containing a spermicidal effective amount of a vanadium (IV) complexes containing a substituted or un-substituted catecholate ligand and a pharmaceutically acceptable carrier, diluent or vehicle. Another aspect of the present invention is a method of contraception including the step of contacting sperm with a spermicidal effective amount of vanadium (IV) complexes containing a substituted or un-substituted catecholate ligand. Preferably, the vanadium (IV) complexes containing a substituted or un-substituted catecholate ligand is complexed with two cyclopentadienyl ligands.